A high-density and high-confinement tokamak plasma regime for fusion energy.

The tokamak approach, utilizing a toroidal magnetic field configuration to confine a hot plasma, is one of the most promising designs for developing reactors that can exploit nuclear fusion to generate electrical energy1,2. To reach the goal of an economical reactor, most tokamak reactor designs3-10 simultaneously require reaching a plasma line-averaged density above an empirical limit-the so-called Greenwald density11-and attaining an energy confinement quality better than the standard high-confinement mode12,13. However, such an operating regime has never been verified in experiments. In addition, a long-standing challenge in the high-confinement mode has been the compatibility between a high-performance core and avoiding large, transient edge perturbations that can cause very high heat loads on the plasma-facing-components in tokamaks. Here we report the demonstration of stable tokamak plasmas with a line-averaged density approximately 20% above the Greenwald density and an energy confinement quality of approximately 50% better than the standard high-confinement mode, which was realized by taking advantage of the enhanced suppression of turbulent transport granted by high density-gradients in the high-poloidal-beta scenario14,15. Furthermore, our experimental results show an integration of very low edge transient perturbations with the high normalized density and confinement core. The operating regime we report supports some critical requirements in many fusion reactor designs all over the world and opens a potential avenue to an operating point for producing economically attractive fusion energy.

Localized mammary gland changes in milk composition and venous blood metabolite concentrations result from sterile subclinical mastitis.

Subclinical mastitis reduces milk yield and elicits undesirable changes in milk composition, but the mechanisms resulting in reduced milk production in affected mammary glands are incompletely understood. This study investigated the effects of sterile inflammation on mammary gland metabolism by assessing changes in milk and venous blood composition. Mid-lactation primiparous Holstein cows (n = 4) had udder halves randomly allocated to treatments; quarters of 1 udder half were infused with 2 billion cfu of formalin fixed Staphylococcus aureus (FX-STAPH) and quarters of the opposite udder half infused with saline (SAL). Blood samples were collected from the right and left subcutaneous abdominal veins in 2.6 h intervals until 40 h post challenge and analyzed for blood gas and metabolite concentrations. Milk from FX-STAPH udder halves had significantly increased SCS by first milking at 8 h post-challenge. By 16 h post-challenge, FX-STAPH udder halves had increased concentrations of protein and lactate and lower lactose concentrations than SAL udder halves. Milk fat concentrations, milk yields, energy corrected milk yields, and the ferric reducing antioxidant power of milk were not significantly different between SAL and FX-STAPH udder halves. Venous blood of FX-STAPH halves had marginally greater concentrations of saturated O2, partial pressures of O2, and glucose concentrations than SAL halves. Conversely, total and partial pressures of CO2 did not differ between udder half treatments suggesting a shift in local metabolite utilization in FX-STAPH udder halves. These results indicate that changes in milk composition resulting from mastitis are accompanied by changes in some key blood metabolite concentrations. The shift in venous blood metabolite concentrations, along with the marked increase in milk lactate, suggests that local mammary tissue and/or recruited and immune cells alters metabolite usage in mammary tissues. Future studies are needed to quantify the uptake of key milk precursors during mastitis.

A multi-centre retrospective study of Nocardia speciation and antimicrobial susceptibility in Queensland, Australia.

The study aims to characterise the species identification and antimicrobial susceptibility testing (AST) results of Nocardial isolates from adult patients across major public hospitals in Queensland, Australia, over a 15-year period. A multi-centre retrospective observational study of Nocardia sp. isolates was conducted from 7 major public hospitals in Queensland, Australia, over a 15-year period. Clinical samples from patients aged ≥ 18 years that isolated Nocardia sp. were included. Demographic and clinical data were collected, along with species identification and AST results. Overall, 484 Nocardia sp. were isolated. Most patients were male (297, 61%) with a mean (IQR) age of 60 (51-75) and a median (IQR) Charlson Comorbidity Index of 4 (2-6). Of these, 239 (49%) patients were immunosuppressed. Organisms were most frequently isolated from sputum (174, 36%), and superficial swabs (102, 21%). Patients presented with pulmonary infections (165, 35%) and superficial skin and soft tissue infections (87, 18%) most commonly. One hundred (21%) isolates were deemed pulmonary colonisation and were not treated. Of the speciated organisms, N. nova complex was the most common (93, 19%), followed by N. farcinica complex (79, 16%). Organisms were reliably susceptible to linezolid (240/245, 98%), amikacin (455/470, 97%), and trimethoprim/sulfamethoxazole (459/476, 96%), but less so to imipenem (243/472, 51%) and ceftriaxone (261/448, 58%). This is the largest Australian description of Nocardia sp. to date. Given antimicrobials are often commenced prior to AST results and sometimes even speciation, characterisation of local species and antibiogram data is important to guide empiric choices and local guidelines.

A split influenza vaccine formulated with a combination adjuvant composed of alpha-D-glucan nanoparticles and a STING agonist elicits cross-protective immunity in pigs.

BACKGROUND: Swine influenza A viruses (SwIAVs) pose an economic and pandemic threat, and development of novel effective vaccines is of critical significance. We evaluated the performance of split swine influenza A virus (SwIAV) H1N2 antigens with a plant-derived nanoparticle adjuvant alone (Nano-11) [Nano11-SwIAV] or in combination with the synthetic stimulator of interferon genes (STING) agonist ADU-S100 (NanoS100-SwIAV). Specific pathogen free (SPF) pigs were vaccinated twice via intramuscular (IM) or intradermal (ID) routes and challenged with a virulent heterologous SwIAV H1N1-OH7 virus. RESULTS: Animals vaccinated IM or ID with NanoS100-SwIAV had significantly increased cross-reactive IgG and IgA titers in serum, nasal secretion and bronchoalveolar lavage fluid at day post challenge 6 (DPC6). Furthermore, NanoS100-SwIAV ID vaccinates, even at half the vaccine dose compared to their IM vaccinated counterparts, had significantly increased frequencies of CXCL10+ myeloid cells in the tracheobronchial lymph nodes (TBLN), and IFNγ+ effector memory T-helper/memory cells, IL-17A+ total T-helper/memory cells, central and effector memory T-helper/memory cells, IL-17A+ total cytotoxic T-lymphocytes (CTLs), and early effector CTLs in blood compared with the Nano11-SwIAV group demonstrating a potential dose-sparing effect and induction of a strong IL-17A+ T-helper/memory (Th17) response in the periphery. However, the frequencies of IFNγ+ late effector CTLs and effector memory T-helper/memory cells, IL-17A+ total CTLs, late effector CTLs, and CXCL10+ myeloid cells in blood, as well as lung CXCL10+ plasmacytoid dendritic cells were increased in NanoS100-SwIAV IM vaccinated pigs. Increased expression of IL-4 and IL-6 mRNA was observed in TBLN of Nano-11 based IM vaccinates following challenge. Furthermore, the challenge virus load in the lungs and nasal passage was undetectable in NanoS100-SwIAV IM vaccinates by DPC6 along with reduced macroscopic lung lesions and significantly higher virus neutralization titers in lungs at DPC6. However, NanoS100-SwIAV ID vaccinates exhibited significant reduction of challenge virus titers in nasal passages and a remarkable reduction of challenge virus in lungs. CONCLUSIONS: Despite vast genetic difference (77% HA gene identity) between the H1N2 and H1N1 SwIAV, the NanoS100 adjuvanted vaccine elicited cross protective cell mediated immune responses, suggesting the potential role of this combination adjuvant in inducing cross-protective immunity in pigs.

Organization of mammary blood vessels as affected by mammary parenchymal region and estradiol administration in Holstein heifer calves.

Mammary blood flow is central to mammary growth, development, and productivity, but the development of the vasculature network is poorly understood. The objective of this study was to determine how the vascular system adapts to mammary growth by inducing different levels of mammary growth and examining 2 regions of mammary parenchymal tissue. Holstein heifer calves (n = 12) received daily injections on the days immediately preceding euthanasia at 82 d of age. Treatments were control (CON), short-term estradiol (STE), and long-term estradiol (LTE). The CON calves received corn oil injections, the STE calves received 9 injections of corn oil followed by 3 injections of estradiol, and the LTE calves received 12 estradiol injections. Mammary tissues were collected from the center and edge parenchymal regions of all right rear mammary glands to quantify the tissue area of various tissue structures, the percentage of proliferating epithelial cells, and the number and form of blood vessels. Results showed that LTE calves had a greater tissue area occupied by epithelium than CON and STE calves, and the epithelial area in CON and STE calves was similar. Edge parenchyma had a greater percentage of proliferating epithelial cells than center parenchyma across all treatment groups. In the edge region, LTE calves had the greatest percentage of proliferating epithelial cells, coinciding with greater epithelial area. The number of blood vessels per unit of tissue area was greater in center than in edge parenchyma; the corresponding vessel surface area per unit of tissue area followed the same pattern. Mammary blood vessel measures were not markedly influenced by estradiol treatment. These results highlight the marked difference in the number and organization of blood vessels in different mammary parenchyma regions but indicate that the effects of estradiol on stimulating mammary epithelial proliferation does not directly translate to increasing numbers of blood vessels.

[Novel drug targets and therapeutic perspectives. Towards a precision medicine]. / Nouvelles cibles et perspectives thérapeutiques. Vers une médecine de précision.

A therapeutic target can be defined as the biochemical entity by which a drug exerts its beneficial effects. Historically, most drugs have been used without a precise knowledge of their mechanism of action. The rational drug design for a predefined target has been progressively implemented during the second half of the 20th century. Recent advances in genomics have accelerated the discovery of several targets involved in many pathologies. During the recent period, there has also been a diversification of the types of targets used in therapy. Generally, the proteins modulated by drugs belonged mainly to the families of membrane receptors (receptors coupled to G proteins, ion channels, etc.), nuclear receptors or enzymes. Technological advances in the field of therapeutic antibodies and biotechnologies enabled curative agents to reach previously undruggable targets. In this article, we review these trends and illustrate them by various examples, notably in the field of anticancer drugs, lipid-lowering drugs, gene therapy or antisense therapy.

Une cible thérapeutique est l'entité biochimique grâce à laquelle les substances actives des médicaments exercent leurs effets bénéfiques. Historiquement, la plupart des médicaments ont été utilisés sans que l'on connaisse leur mécanisme d'action. La conception rationnelle de thérapies créées pour agir spécifiquement sur une cible définie à l'avance s'est développée au cours de la seconde moitié du XXème siècle. Les progrès de la génomique ont accéléré la découverte de plusieurs cibles impliquées dans de nombreuses pathologies. Au cours de la période récente, on constate également une diversification de la nature des cibles sur lesquelles agissent les médicaments. Généralement, les protéines contre lesquelles était dirigé l'arsenal thérapeutique appartenaient majoritairement aux familles des récepteurs membranaires (récepteurs couplés aux protéines G, canaux ioniques,…), des récepteurs nucléaires ou bien des enzymes. Les avancées technologiques dans le domaine des anticorps thérapeutiques et des biotechnologies permettent, à présent, de diriger des agents thérapeutiques vers des macromolécules jugées inutilisables auparavant. Dans cet article, nous passons en revue ces tendances illustrées par différents exemples, dans le domaine, notamment, des anticancéreux, des hypolipidémiants, de la thérapie génique ou antisens.

A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1.

Beclabuvir is a potent, non-nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa-2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double-blinded, placebo-controlled, dose-ranging phase 2a study, 39 treatment-naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 µg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [≥ 75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow-up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150-mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all-oral regimen for HCV GT1.

Observation of a multimode plasma response and its relationship to density pumpout and edge-localized mode suppression.

Density pumpout and edge-localized mode (ELM) suppression by applied n=2 magnetic fields in low-collisionality DIII-D plasmas are shown to be correlated with the magnitude of the plasma response driven on the high-field side (HFS) of the magnetic axis but not the low-field side (LFS) midplane. These distinct responses are a direct measurement of a multimodal magnetic plasma response, with each structure preferentially excited by a different n=2 applied spectrum and preferentially detected on the LFS or HFS. Ideal and resistive magneto-hydrodynamic (MHD) calculations find that the LFS measurement is primarily sensitive to the excitation of stable kink modes, while the HFS measurement is primarily sensitive to resonant currents (whether fully shielding or partially penetrated). The resonant currents are themselves strongly modified by kink excitation, with the optimal applied field pitch for pumpout and ELM suppression significantly differing from equilibrium field alignment.

Titanium carbenoid-mediated cyclopropanation of allylic alcohols: selectivity and mechanism.

A new method for the chemo- and stereoselective conversion of allylic alcohols into the corresponding cyclopropane derivatives has been developed. The cyclopropanation reaction was carried out with an unprecedented titanium carbenoid generated in situ from Nugent's reagent, manganese and methylene diiodide. The reaction involving the participation of an allylic hydroxyl group, proceeded with conservation of the alkene geometry and in a high diastereomeric excess. The scope, limitations and mechanism of this metal-catalysed reaction are discussed.

The synthesis of 3-hydroxy-2,4,8-trimethyldec-8-enolides and an approach to 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide.

The synthesis of several derivatives of 3-hydroxy-2,4,8-trimethyldec-8-enolide and attempts at the synthesis of 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (1), a structure which has been assigned to a metabolite of the phytopathogenic fungus, Botrytis cinerea, gave products whose spectroscopic data had significant differences from those reported for the natural product 1. The rare 11-membered lactone rings were constructed by ring-closing metathesis reactions. The increase in conformational restrictions imposed by the substituents has a high influence on the stereochemistry of the ring-closing metathesis reaction and gives rise to a decrease in the yield for the synthesis of 11-membered lactones. The predominant alkene which was obtained was the (Z)-isomer. The observed spectroscopic differences between the synthesized lactones and the natural product and the spectroscopic data of its acetylated derivative 26a allowed us to revise the structure 1 to that of the γ-butyrolactone 26.

Bacterial community composition of three candidate insect vectors of palm phytoplasma (Texas Phoenix Palm Decline and Lethal Yellowing).

Texas Phoenix Palm Decline (TPPD) and Lethal Yellowing are two phytoplasma-linked diseases in palms. The phytoplasma causing TPPD is thought to be transmitted by three putative planthopper vectors, Ormenaria rufifascia, Omolicna joi, and Haplaxius crudus. These insects have been morphologically and molecularly described, and have screened positive for Candidatus Phytoplasma palmae. Individuals from each species were subjected to 16S bacterial community sequencing using the Roche 454 platform, providing new information regarding the previously unexplored bacterial communities present in putative vectors.

Tokamak operation with safety factor q95 < 2 via control of MHD stability.

Magnetic feedback control of the resistive-wall mode has enabled the DIII-D tokamak to access stable operation at safety factor q(95) = 1.9 in divertor plasmas for 150 instability growth times. Magnetohydrodynamic stability sets a hard, disruptive limit on the minimum edge safety factor achievable in a tokamak, or on the maximum plasma current at a given toroidal magnetic field. In tokamaks with a divertor, the limit occurs at q(95) = 2, as confirmed in DIII-D. Since the energy confinement time scales linearly with current, this also bounds the performance of a fusion reactor. DIII-D has overcome this limit, opening a whole new high-current regime not accessible before. This result brings significant possible benefits in terms of fusion performance, but it also extends resistive-wall mode physics and its control to conditions never explored before. In present experiments, the q(95) < 2 operation is eventually halted by voltage limits reached in the feedback power supplies, not by intrinsic physics issues. Improvements to power supplies and to control algorithms have the potential to further extend this regime.

Exploring mutasynthesis to increase structural diversity in the synthesis of highly oxygenated polyketide lactones.

The enantioselective synthesis of (2R,3R,4E,8E)-3-hydroxy-2,4,8-trimethyldeca-4,8-dienolide (5) by ring-closing metathesis is described. This compound is an analogue of 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (4) which is a rare 11-membered lactone produced by the fungus, Botrytis cinerea. Mutasynthetic studies with compound 5 using two mutants of B. cinerea led to the isolation of four new highly oxygenated 11-membered lactones (11-14) in which compound 5 has been stereoselectively epoxidized and hydroxylated at sites that were not easily accessible by classical synthetic chemistry.

Multilocus Characterization of a Woodrat (Genus Neotoma) Hybrid Zone.

In order to investigate hybridization between 2 species of woodrats, Neotoma floridana and Neotoma micropus, 103 specimens were collected, in March of 1988, from a known area of sympatry, and compared with reference collections from areas of allopatry. Ten genetic markers, consisting of 7 microsatellite loci, 1 mitochondrial gene (cytochrome-b [Cytb]), and 2 nuclear introns (intron 2 of the vertebrate alcohol dehydrogenase gene [Adh1-I2] and intron 7 of the beta-fibrinogen gene [Fgb-I7]) were used to develop a composite genotype for each individual and for detection of hybridization. Six individuals were identified as pure parental N. micropus, 96 as hybrids, and 1 as pure parental N. floridana Hybrids were formed primarily through matings between complex genotypes, resulting in a high prevalence of individuals classified as backcrosses. The ratio of hybrid classes, population substructure, and presence of significant linkage disequilibrium within the zone of contact could not reject either the hybrid superiority or hybrid equilibrium model as responsible for maintenance of this hybrid zone. The collection date of this dataset (1988) provided not only a point in time assessment of the hybrid zone but also provided opportunities for future comparisons of temporal datasets with the purpose of examining hybrid zone characteristics over multiple generations.

Assessment of the risk of salmonellosis from internally contaminated shell eggs following initial storage at 18 °C (65 °F), compared with 7 °C (45 °F).

In the U.S., chicken-breeder farms that supply hatcheries typically store and transport eggs intended for broiler production at a temperature of 18.3 °C (65 °F). However, in case of surplus, some of these eggs may be diverted to human consumption. According to the U.S. Food and Drug Administration's 'Egg Safety Final Rule,' shell eggs intended for human consumption are required to be held or transported at or below 7.2 °C (45 °F) ambient temperature beginning 36 h after time of lay. We adapted a risk assessment model developed by the U.S. Department of Agriculture's Food Safety Inspection Service, to quantify human exposure to Salmonella Enteritidis and the risk of human salmonellosis if eggs are held and transported at 18.3 °C for up to 5.5 days after time of lay, as has been observed when hatchery eggs are diverted to human consumption, rather than held and transported at 7.2 °C within 36 h after time of lay. Storage at 18.3 °C leads to considerable bacterial growth in internally contaminated eggs. The model predicted that more than 10% of internally contaminated eggs would remain contaminated after in-shell pasteurization resulting in a 5-log10 reduction, and that some bacteria would survive after home-cooking. The model predicted that, alternatively, eggs stored at 7.2 °C after lay would have limited bacterial growth prior to pasteurization, and Salmonella would be very unlikely to be present after pasteurization. The predicted risk of salmonellosis from the consumption of eggs held and transported at 18.3 °C and subsequently diverted to human consumption is 25 times higher than the risk when eggs are held and transported at 7.2 °C.

Measurement of muon antineutrino quasielastic scattering on a hydrocarbon target at Eν ~ 3.5 GeV.

We have isolated ν(µ) charged-current quasielastic (QE) interactions occurring in the segmented scintillator tracking region of the MINERvA detector running in the NuMI neutrino beam at Fermilab. We measure the flux-averaged differential cross section, dσ/dQ², and compare to several theoretical models of QE scattering. Good agreement is obtained with a model where the nucleon axial mass, M(A), is set to 0.99 GeV/c² but the nucleon vector form factors are modified to account for the observed enhancement, relative to the free nucleon case, of the cross section for the exchange of transversely polarized photons in electron-nucleus scattering. Our data at higher Q² favor this interpretation over an alternative in which the axial mass is increased.